RELM-β介导信号通路在低氧性肺动脉高压肺动脉平滑肌细胞增殖中的作用及机制研究

Resistin-Like Molecule-β（RELM-β）has been suggested as a mitogenic factor of human lung tissue under hypoxia condition. Recent studies have shown that RELM-β is abundantly expressed on the pulmonary vascular smooth muscle of patients with pulmonary hypertension. RELM-βcan be significant induced by hypoxia and has proliferative effect in pulmonary arterial smooth muscle cells(PASMCs).However,there is still little known about it’s effect and molecular mechanism in hypoxic pulmonary hypertension. The project was designed to study whether hypoxia up-regulate the expression of RELM-βin PASMCs , promote PASMCs proliferation (1) via ERK1/2-NF-κB-Nox4-ROS-pRb-E2F1 pathway and （2）via PLC-IP3 and ROS-[Ca2+]i-Calcineurin-NFATc3 single pathway ;(3)we will further investigate whether interference of RELM-β and it`s downstream targetgene expression alleviates PASMCs proliferation, pulmonary vascular remodeling and hypoxic pulmonary hypertension in animal models. We will test our hypothesis in primary cultured PASMCs ,chronic hypoxia animal models and COPD patient with pulmonary hypertension. The results generated from this project may provide new information on the cellular and molecular mechanism of hypoxic pulmonary hypertension, and identify therapeutic targets for the development of novel treatment for the dreadful disease.

抵抗素样分子-β（Resistin-Like Molecule-β，RELM-β）是一种低氧条件下人肺组织特异性生长因子。研究表明，RELM-β在肺动脉高压患者的肺血管平滑肌上表达升高，且能明显促进肺动脉平滑肌细胞增殖。但其在低氧性肺动脉高压中的作用和机制尚不明确。本项目将探讨低氧能否上调肺动脉平滑肌细胞RELM-β表达，(1)通过ERK1/2-NF-κB/Nox4/ROS/pRb/E2F1以及(2)PLC-IP3和ROS-Ca2+/Calcineurin/NFATc3通路导致肺动脉平滑肌细胞增殖；(3)干预RELM-β及下游通路能否影响低氧性肺动脉高压的发生。本研究将从原代培养的肺动脉平滑肌细胞、低氧性肺动脉高压动物模型和COPD肺动脉高压患者三个方面来验证我们的假设。我们希望通过对HPH病理机制的深入认识，寻找新的防治靶点，改进药物干预方法，从而达到改善预后和治愈这一致死性疾病的目的。

抵抗素样分子-β（Resistin-Like Molecule-β，RELM-β）是一种低氧条件下人肺组织特异性生长因子。本项目对RELM-β在低氧性肺动脉高压中的作用和机制进行了探讨。研究发现低氧可上调RELM-β表达，促进肺动脉平滑肌细胞增殖；且RELM-β在TGF-β1诱导人肺动脉内皮细胞EndMT中起着重要作用，从而介导肺血管重塑发生。RELM-β不仅可通过调控PI3K/Akt/mTOR和PKC、MAPKs信号通路参与大鼠低氧性肺动脉高压肺血管重构；也可通过调控PLC/IP3信号通路参与野百合碱肺动脉高压大鼠模型肺血管重构；还可通过调控PI3K/Akt/mTOR信号通路在COPD相关肺动脉高压患者肺血管重构发生中起重要作用。另外，RELM-β通过调控PLC-IP3/Ca2+/PI3K/Akt/mTOR及Calcineurin/NFATc3信号通路促进低氧性人和大鼠肺动脉平滑肌细胞增殖；也可通过调节PLC-IP3/Ca2+信号通路促进野百合碱致大鼠肺动脉平滑肌增殖。干预RELM-β及其信号通路（PLC-IP3/Ca2+/PI3K/Akt/mTOR及Calcineurin/NFATc3等）表达可以阻逆低氧诱导性肺动脉平滑肌增殖、肺血管重塑和肺动脉高压的发生发展。研究结果加深了对肺动脉高压病理机制的认识，认为RELM-β可能是肺动脉高压的防治靶点。